Experiments investigating the pathogenetic mechanisms of AIDS-associated Kaposi's sarcoma (AIDS-KS) have demonstrated that most of the spindle cells of KS have features of activated endothelial cells. This is consistent with the presence of inflammatory cytokines in KS lesions, particularly gamma-interferon. These cytokines induce normal endothelial cells to acquire the phenotypic and functional features of KS spindle cells including morphology, marker expression, expression of the receptors for Tat, production and release of basic fibroblast growth factor (bFGF), and formation of KS-like lesions after injection in nude mice. In particular, bFGF appears to play a pivotal role in KS lesion formation, and antisense bFGF oligomers and other drugs inhibiting angiogenesis, such as Apolipoprotein-E, demonstrate the potential as therapeutic agents for KS. Related investigations have shown that the Tat protein of HIV-1 mimics the effect of extracellular matrix protein, and via binding to integrin receptors induces growth, migration and invasion of KS cells and activated endothelial cells. As for other extracellular matrix proteins, Tat increases the effect of bFGF and synergizes with this cytokine in inducing KS lesion formation. These results indicate that, at least in its early stage, KS is a hyperplastic proliferative disease driven by cytokines and angiogenic factors. In this setting Tat increases the frequency and aggressiveness of AIDS-KS by enhancing cell growth and angiogenesis. A novel herpesvirus recently detected in KS lesions may be responsible for the local increase in inflammatory cytokines which may trigger lesion formation.